virology blog
About viruses and viral disease
By Gertrud U. Rey
Quorum sensing is a form of cell to cell communication in bacteria in which individual cells coordinate their behavior based on population density. In human terms, the word “quorum” means “the minimum number of people required to conduct business.”
The TWiV team travels to Texas A&M University, home of the Center for Phage Technology, where they speak with Ry Young and Jason Gill about their work on viruses that infect bacteria.
Click arrow to play
Download TWiV 502 (54 MB .mp3, 90 min)
Subscribe (free): iTunes, Google Podcasts, RSS, email
Become a patron of TWiV!
Show notes at microbe.tv/twiv
Virologist Roger W. Hendrix died on 15 August 2017. I only met Roger once, at the 2011 ASM meeting in New Orleans where we recorded an episode of This Week in Virology. The video of that episode is below, starting at my conversation with Roger at 30:34. Harmit Malik and Rachel Katzenellenbogen were my other guests on TWiV 135.
Not long after their discovery, viruses that infect bacteria – bacteriophages – were considered as therapeutic agents for treating infections. Despite many years of research on so-called phage therapy, clinical trials have produced conflicting results. They might be explained in part by the results of a new study which show that the host innate immune system is crucial for the efficacy of phage therapy.
When mice are infected intranasally with Pseudomonas aeruginosa (which causes pneumonia in patients with weak immune systems), the bacterium multiplies in the lungs and kills the animals in less than two days. When a P. aeruginosa lytic phage (i.e. that kills the bacteria) is instilled in the nose of the mice two hours after bacterial infection, all the mice survive and there are no detectable bacteria in the lungs. The phage can even be used prophylactically: it can prevent pneumonia when given up to four days before bacterial challenge.
The ability of phage to clear P. aeruginosa infection in the mouse lungs depends on the innate immune response. When bacteria infect a host, they are rapidly detected by pattern recognition receptors such as toll-like receptors. These receptors detect pathogen-specific molecular patterns and initiate a signaling cascade that leads to the production of cytokines, which may stop the infection. Phage cannot clear P. aeruginosa infection in mice lacking the myd88 gene, which is central to the activity of toll like receptors. This result shows that the innate immune response is crucial for the ability of phages to clear bacterial infections. In contrast, neither T cells, B cells, or innate lymphoid cells such as NK cells are needed for phage therapy to work.
The neutrophil is a cell of the immune system that is important in curtailing bacterial infections. Phage therapy does not work in mice depleted of neutrophils. This result suggests that humans with neutropenia, or low neutrophil counts, might not respond well to phage therapy.
A concern with phage therapy is that bacterial mutants resistant to infection might arise, leading to treatment failure. In silico modeling indicated that phage-resistant bacteria are eliminated by the innate immune response. In contrast, phage resistant bacteria dominate the population in mice lacking the myd88 gene.
These results demonstrate that in mice, successful phage therapy depends on a both the innate immune response of the host, which the authors call ‘immunophage synergy’. Whether such synergy also occurs in humans is not known, but should be studied. Even if observed in humans, immunophage synergy might not be a feature of infections in other anatomical locations, or those caused by other bacteria. Nevertheless, should immunophage synergy occur in people, then clearly only those with appropriate host immunity – which needs to be defined – should be given phage therapy.